COX-2 KO mice injected intraperitoneally with NMDA (25-100 mg/kg) exhibited significantly increased median seizure intensity when compared to WT mice. Further, COX-2 KO mice exposed to NMDA showed neuronal damage, detected by Fluoro Jade B (FJB) staining, in the CA3 region of the hippocampus. There was no FJB staining nor any significant difference in median or maximal seizure intensity in COX-2 WT and KO mice exposed to lindane. LC-MS/MS analysis of brain prostaglandin profile in COX-2-/- mice demonstrated a significant increase in PGF2, TXB2, PGE2 and PGD2 expression 1 hour after administration of an excitotoxic dose of KA, but not of NMDA. Our findings demonstrate that COX-2 regulates susceptibility to KA and NMDA excitotoxicity, which directly activate glutamatergic neurotransmission, but not to lindane, which indirectly alters glutamatergic neurotransmission. Furthermore, increased levels of prostaglandins after seizures are associated with consistent evidence of neuronal damage.